Ischemic Heart Disease
Ischemia occurs when an artery supplying oxygenated blood to a muscle or other organ becomes occluded. This diminishes the ability of the affected organ to function and may involve cell death in the area whose blood supply is reduced.
Ischemic heart disease is a major cause of death. Even in those patients who survive a heart attack, the prospects of an active lifestyle are severely reduced due to the loss of cardiac muscle. Cardiac muscle, like skeletal muscle and the central nervous system, is a post-mitotic tissue. As there is virtually no cell replacement throughout life, there has to be an effective ongoing local repair mechanism. Local physical and free radical damage occurs even in healthy tissues and has to be repaired; otherwise the cell undergoes cell death that results in a permanent functional deficit.
In the heart, ischemia can result from an obstruction of the coronary arteries. This leads to cardiomyocytes in certain areas becoming deprived of blood and thus oxygen. They then commence to die. This means increased mechanical strain on the surviving myocardiocytes in the area becoming damaged, which also leads to cell death. Thus, cell death occurs both as a result of oxygen deprivation and as a result of undue mechanical strain. The region of cell death, or necrosis, is known as an infarct.
The MGF Splice Variant of IGF-I
Mammalian IGF-I polypeptides have a number of isoforms, which arise as a result of alternative mRNA splicing. Broadly, there are two types of isoform, liver-type isoforms and non-liver-type ones. Liver-type isoforms may be expressed in the liver or elsewhere but, if expressed elsewhere, are equivalent to those expressed in the liver. They have a systemic action and are the main isoforms in mammals. Non-liver-type isoforms are less common and some are believed to have an autocrine/paracrine action. The MGF isoform of the invention is of the latter type. The terminology for the IGF-I splice variants is based on the liver isoforms (Chew et al, 1995) and has not fully evolved to take into account those produced by non-liver tissues. The latter are controlled to some extent by a different promoter (promoter 1) to the liver IGF-I isoforms, which respond to hormones and are under the control of promoter 2.
In human skeletal muscle, we have cloned the cDNA of three IGF-I splice variants. With reference to FIG. 1, exons 1 and 2 are alternative leader exons with distinct transcription start sites which are differentially spliced to common exon 3. Exons 3 and 4 code for the mature IGF-I peptide (B, C, A and D domains) as well as the first 16 amino acids of the E domain. Exons 5 and 6 each encode an alternative part of a distinct extension peptide, the E domain. This is followed by the termination codons of precursor IGF-I, 3′ untranslated regions and poly(A) addition signal sites.
In skeletal muscle, the mRNA of one of the three muscle IGF-I splice variants was only detectable in exercised and/or in damaged (stretched and/or electrically stimulated) muscle, and its expression is related to the level of muscle activity. We have named it Mechano Growth Factor (MGF). MGF mRNA is not detected in dystrophic skeletal muscle even when it is subjected to stretch.
MGF (FIG. 1; Yang et al, 1996; McKoy et al, 1999) has exons 4, 5 and 6 whilst the muscle-expressed liver-type IGF-I has exons 4 and 6. The other two splice variants found in human muscle have similar sequences to the liver systemic type of IGF-I. Notably, human MGF has a 49 base pair insert (E domain) which changes its reading frame at the carboxy end.
We have already identified MGF for the treatment of disorders of skeletal muscle, notably muscular dystrophy (WO97/33997; U.S. Pat. No. 6,221,842; Yang et al, 1996; McKoy et al, 1999), for the treatment of neurological disorders (WO01/136483) and for nerve repair (WO01/85781).